About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

May 9, 2013

Your Brain Shifts Gears

Posted by Derek

Want to be weirded out? Study the central nervous system. I started off my med-chem career in CNS drug discovery, and it's still my standard for impenetrability. There's a new paper in Science, though, that just makes you roll your eyes and look up at the ceiling.

The variety of neurotransmitters is well appreciated - you have all these different and overlapping signaling systems using acetylcholine, dopamine, serotonin, and a host of lesser-known molecules, including such oddities as hydrogen sulfide and even carbon monoxide. And on the receiving end, the various subtypes of receptors are well studied, and those give a tremendous boost to the variety of signaling from a single neurotransmitter type. Any given neuron can have several of these going on at the same time - when you consider how many different axons can be sprawled out from a single cell, there's a lot of room for variety.

That, you might think, is a pretty fair amount of complexity. But note also that the density and population of these receptors can change according to environmental stimuli. That's why you get headaches if you don't have your accustomed coffee in the morning (you've made more adenosine A2 receptors, and you haven't put any fresh caffeine ligand into them). Then there are receptor dimers (homo- and hetero-) that act differently than the single varieties, constituitively active receptors that are always on, until a ligand turns them off (the opposite of the classic signaling mechanism), and so on. Now, surely, we're up to a suitable level of complex function.

Har har, says biology. This latest paper shows, by a series of experiment in rats, that a given population of neurons can completely switch the receptor system it uses in response to environmental cues:

Our results demonstrate transmitter switching between dopamine and somatostatin in neurons in the adult rat brain, induced by exposure to short- and long-day photoperiods that mimic seasonal changes at high latitudes. The shifts in SST/dopamine expression are regulated at the transcriptional level, are matched by parallel changes in postsynaptic D2R/SST2/4R expression, and have pronounced effects on behavior. SST-IR/TH-IR local interneurons synapse on CRF-releasing cells, providing a mechanism by which the brain of nocturnal rats generates a stress response to a long-day photoperiod, contributing to depression and serving as functional integrators at the interface of sensory and neuroendocrine responses.

This remains to be demonstrated in human tissue, but I see absolutely no reason what the same sort of thing shouldn't be happening in our heads as well. There may well be a whole constellation of these neurotransmitter switchovers that can take place in response to various cues, but which neurons can do this, involving which signaling regimes, and in response to what stimuli - those are all open questions. And what the couplings are between the environmental response and all the changes in transcription that need to take place for this to happen, those are going to have to be worked out, too.

There may well be drug targets in there. Actually, there are drug targets everywhere. We just don't know what most of them are yet.

As Haldane would say, "Not only is the neuron queerer than we suppose, but it is queerer than we can suppose".

What makes the neurotransmitter GPCRs even more complex is the phenomenon of functional selectivity that can cause the same kind of molecule (two agonists for instance) to activate two completely different signaling pathways.

I mean, Seasonal Affective Disorder has been known about for quite a while, as well as the fact that light therapy works to treat it. Or is that disqualified for some reason?

@3: Snark it up all you wish, some environmental changes work better than getting stuffed full of pills for some problems. Light therapy to deal with SAD and various sleeping disorders for example. Here in the Nordic countries, we have a couple of decades of experience of it at the very least....

Back to the topic at hand, as Derek says, the real work will be to map out everything, without falling into the trap of coming up with overly simplistic models. I'm very curious about what causes the sensory changes in people with Aspergers for example, or how ADHD can be so "seasonal" and tied to external stimuli such as music Personal anecdote time: I suffer from ADHD, and so-called "Relaxation music" tends to drive me nuts, while speed or death metal, or hard and fast EBM, can make me calm down and focus. And it's not the fact that it shuts out other sounds, I can play it as background music while talking to someone, and it has that calming effect.

Derek saved me the trouble of writing this one up. It would be reason #23 of why drug discovery is so hard, and why big pharma sheds chemists. It may be why drugs for/against a particular transmitter work well some of the time, and have adverse effects at other times.

It seems like the most direct approach to seasonal affective disorder would be migration. Anybody want to offer me a dual-location position where I spend summers in Denmark and antipodal summers in New Zealand?

Re: 5

Brains often work as stochastic amplifiers, so adding a level of stimulating noise to the signal could be raising it above your detection threshold.

Those circadian rhythm effects are horribly complex: light reception takes place in one place in the brain (melanopsin) and the master pacemaker is in another region (SCN). Moreover, all major organs have their own cellular clock.
What is secreted, how, by whom? Good question... But well, it can mess up a lot from sleep to metabolism. Now add expressional control of receptor/neurotransmitter (of a certain neuron subtypes) to the list.

Don't forget one final layer of complexity ... Polymorphism! Humans vary enormously in the sequence, expression, and function of most of the neuroreceptors mentioned above... Different strokes for different folks, especially when it comes to CNS drugs!

While understanding the human brain is admittedly a daunting task, paradoxically, it becomes easier once one acknowledges brain function is far more complex than a series of communications among synaptically connected neurons. CNS macroglia (astrocytes, oligodendrocytes, and NG2 glia, the latter a.k.a. oligodendrocyte progenitor cells) express most--if not all--the same neurotransmitter receptors expressed on neurons. Thus, these macroglial cells are intimately and actively involved in the "conversations" that drive brain function: see, for example, the work of Philip G. Haydon in elaborating the concept of the "tripartite synapse."

The 2010 R. Douglas Fields book The Other Brain also provides an eye-opening look at how deciphering the role of glia in brain function is revolutionizing our understanding of the CNS in health and disease. This book IS required reading for anyone trying to discover next generation CNS drugs.